Activity-dependent Plasticity Research Articles

Beyond antiviral: role of IFN-I in brain development

Interferons and central nervous system resident macrophages, microglia, are well-known for their respective roles in antiviral defense and phagocytosis. Using a classic experimental paradigm for examining activity-dependent neural plasticity, Escoubas, Dorman, et al. recently identified a role for microglial type I interferon signaling in the clearance of unwanted neurons during mouse brain development.

Gene expression variation in geographically diverse populations of two North American songbird species

The range distributions of many bird species cover extensive geographic distances, exposing each local population to unique ecological challenges. Understanding the molecular basis of how species adapt to diverse habitats across their geographic range is crucial for identifying populations at risk and implementing effective conservation strategies. In this study, we employed two passerine species, the black-capped chickadee (Poecile atricapillus) and the American goldfinch (Spinus tristis), which are widely distributed across North America. This study focused on examining changes in gene expression within their distinct populations inhabiting diverse habitats across various geographical locations. A comparative transcriptomic study was conducted on wild-caught birds from two geographically separate locations, Boston, Massachusetts, and Kent, Ohio, characterized by considerable annual variability in winter severity. We tested the hypothesis that populations of both species in Kent and Boston would show differential gene expression patterns in their brains in response to unique local environmental conditions. Analyzing the differentially expressed genes (DEGs) in black-capped chickadees revealed associations with neural processes such as the generation and maintenance of neurons, activity-dependent plasticity, and cognitive ability. Many of these genes were linked to brain variation in chickadee populations related to spatial cognition associated with food caching. We also compared changes in gene expression levels with coding sequence variability to explore the underlying basis of differential gene expression patterns. We tested the hypothesis that expression differences are driven by underlying genetic variation. A population genetic analysis on transcriptome data from both species revealed no highly divergent genetic variants (single nucleotide polymorphisms or SNPs) in the coding regions of genes identified as differentially expressed. However, some of the DEGs themselves were transcription factors or regulatory molecules, as were some of the genes with highly divergent SNPs. These findings suggest that the genetic architecture underlying the differential gene expression patterns is mostly regulatory rather than protein-coding changes.

The Wingless planar cell polarity pathway is essential for optimal activity-dependent synaptic plasticity.

From fly to man, the Wingless (Wg)/Wnt signaling molecule is essential for both the stability and plasticity of the nervous system. The Drosophila neuromuscular junction (NMJ) has proven to be a useful system for deciphering the role of Wg in directing activity-dependent synaptic plasticity (ADSP), which, in the motoneuron, has been shown to be dependent on both the canonical and the noncanonical calcium Wg pathways. Here we show that the noncanonical planar cell polarity (PCP) pathway is an essential component of the Wg signaling system controlling plasticity at the motoneuron synapse. We present evidence that disturbing the PCP pathway leads to a perturbation in ADSP. We first show that a PCP-specific allele of disheveled (dsh) affects the de novo synaptic structures produced during ADSP. We then show that the Rho GTPases downstream of Dsh in the PCP pathway are also involved in regulating the morphological changes that take place after repeated stimulation. Finally, we show that Jun kinase is essential for this phenomenon, whereas we found no indication of the involvement of the transcription factor complex AP1 (Jun/Fos). This work shows the involvement of the neuronal PCP signaling pathway in supporting ADSP. Because we find that AP1 mutants can perform ADSP adequately, we hypothesize that, upon Wg activation, the Rho GTPases and Jun kinase are involved locally at the synapse, in instructing cytoskeletal dynamics responsible for the appearance of the morphological changes occurring during ADSP.

Neuroplasticity in the pathogenesis and treatment of chronic pain syndrome: new research and therapeutic perspectives

Recent research and therapeutic outlooks examine the impact of neuroplasticity on the progression and management of chronic pain syndrome. Aims: To review neurobiological basis as well as neuroplastic mechanisms in chronic pain syndrome, exploring bidirectional relationship and innovative therapies and to evaluate efficacy/safety of diverse treatments like TENS, rTMS, pharmacotherapies, and exercise in chronic pain management. Study design: A narrative literature review. Place and Duration of Study: 2019 to 2024. Methodology: A narrative review was conducted using the keywords “Neuroplasticity" AND "Chronic Pain" on PubMed yielded a total of 333 publications. Out of the total publications, 21 were deemed directly relevant, probably providing valuable perspectives on the link between neuroplasticity and chronic pain. Results: Results showed that out of the 11 studies analysed, 7 investigated the bidirectional relationship between chronic pain and neuroplasticity. Additionally, 4 studies reviewed pharmacological methods, 2 studies discussed personalised management and mechanistic profiling, and 7 explored neuromodulation and non-pharmacological interventions. Various neurophysiological correlates of chronic pain were studied, including somatosensory and cortical neurophysiology profiles but Central sensitisation and neuroinflammation were the explored key mechanisms. Activity-dependent plasticity, neuroplasticity in pain modulation, and cortical plasticity are extensively explored, revealing changes in neural activity, synaptic strength, and brain structure. Research explores the connection between chronic pain and neuroplasticity, examining how they impact each other and highlighting the constant interaction between pain perception and neural plasticity. Innovative therapeutic strategies include neuromodulation techniques, pharmacological interventions, personalised pain management, and multimodal approach. Non-invasive brain stimulation, transcutaneous electrical nerve stimulation , and home-based focused tDCS show promise in chronic pain management. Conclusion: In summary, these findings highlighted the multifaceted nature of chronic pain and the on-going efforts to develop effective therapeutic interventions, showcasing a dynamic field of research aiming to improve the lives of those suffering from chronic pain.

Targeting epigenetic mechanisms in amyloid-β-mediated Alzheimer's pathophysiology: unveiling therapeutic potential.

Alzheimer's disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia. Growing evidence suggests that Alzheimer's disease is associated with accumulating various amyloid-β oligomers in the brain, influenced by complex genetic and environmental factors. The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer's disease are believed to primarily result from synaptic dysfunction. Throughout life, environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders. These changes, known as epigenetic modifications, also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity. In this context, we highlight recent advances in understanding the roles played by key components of the epigenetic machinery, specifically DNA methylation, histone modification, and microRNAs, in the development of Alzheimer's disease, synaptic function, and activity-dependent synaptic plasticity. Moreover, we explore various strategies, including enriched environments, exposure to non-invasive brain stimulation, and the use of pharmacological agents, aimed at improving synaptic function and enhancing long-term potentiation, a process integral to epigenetic mechanisms. Lastly, we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer's disease. We suggest that addressing Alzheimer's disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.

DeepD3, an open framework for automated quantification of dendritic spines.

Dendritic spines are the seat of most excitatory synapses in the brain, and a cellular structure considered central to learning, memory, and activity-dependent plasticity. The quantification of dendritic spines from light microscopy data is usually performed by humans in a painstaking and error-prone process. We found that human-to-human variability is substantial (inter-rater reliability 82.2±6.4%), raising concerns about the reproducibility of experiments and the validity of using human-annotated 'ground truth' as an evaluation method for computational approaches of spine identification. To address this, we present DeepD3, an open deep learning-based framework to robustly quantify dendritic spines in microscopy data in a fully automated fashion. DeepD3's neural networks have been trained on data from different sources and experimental conditions, annotated and segmented by multiple experts and they offer precise quantification of dendrites and dendritic spines. Importantly, these networks were validated in a number of datasets on varying acquisition modalities, species, anatomical locations and fluorescent indicators. The entire DeepD3 open framework, including the fully segmented training data, a benchmark that multiple experts have annotated, and the DeepD3 model zoo is fully available, addressing the lack of openly available datasets of dendritic spines while offering a ready-to-use, flexible, transparent, and reproducible spine quantification method.

Transient demyelination causes long-term cognitive impairment, myelin alteration and network synchrony defects.

In the adult brain, activity-dependent myelin plasticity is required for proper learning and memory consolidation. Myelin loss, alteration, or even subtle structural modifications can therefore compromise the network activity, leading to functional impairment. In multiple sclerosis, spontaneous myelin repair process is possible, but it is heterogeneous among patients, sometimes leading to functional recovery, often more visible at the motor level than at the cognitive level. In cuprizone-treated mouse model, massive brain demyelination is followed by spontaneous and robust remyelination. However, reformed myelin, although functional, may not exhibit the same morphological characteristics as developmental myelin, which can have an impact on the activity of neural networks. In this context, we used the cuprizone-treated mouse model to analyze the structural, functional, and cognitive long-term effects of transient demyelination. Our results show that an episode of demyelination induces despite remyelination long-term cognitive impairment, such as deficits in spatial working memory, social memory, cognitive flexibility, and hyperactivity. These deficits were associated with a reduction in myelin content in the medial prefrontal cortex (mPFC) and hippocampus (HPC), as well as structural myelin modifications, suggesting that the remyelination process may be imperfect in these structures. In vivo electrophysiological recordings showed that the demyelination episode altered the synchronization of HPC-mPFC activity, which is crucial for memory processes. Altogether, our data indicate that the myelin repair process following transient demyelination does not allow the complete recovery of the initial myelin properties in cortical structures. These subtle modifications alter network features, leading to prolonged cognitive deficits in mice.

Pairing taVNS and CIMT is feasible and may improve upper extremity function in infants.

In this study we combined non-invasive transcutaneous auricular vagal nerve stimulation (taVNS) with 40 h of constraint induced movement therapy (CIMT) in infants. All infants completed the full intervention with no adverse events. Therapists were able to maintain high treatment fidelity and reported high ratings for ease of use and child tolerance. Preliminary results show promising gains on motor outcomes: Mean QUEST increase 19.17 (minimal clinically important difference, MCID 4.89); Mean GMFM increase 13.33 (MCID 1%-3%). Infants also exceeded expectations on Goal Attainment Scores (+1). Early data is promising that taVNS paired with intensive motor CIMT is feasible, reliable, and safe in young infants with hemiplegia, and may help harness activity-dependent plasticity to enhance functional movement.

Versatile Endogenous Editing of GluRIIA in Drosophila melanogaster.

Glutamate receptors at the postsynaptic side translate neurotransmitter release from presynapses into postsynaptic excitation. They play a role in many forms of synaptic plasticity, e.g., homeostatic scaling of the receptor field, activity-dependent synaptic plasticity and the induction of presynaptic homeostatic potentiation (PHP). The latter process has been extensively studied at Drosophila melanogaster neuromuscular junctions (NMJs). The genetic removal of the glutamate receptor subunit IIA (GluRIIA) leads to an induction of PHP at the synapse. So far, mostly imprecise knockouts of the GluRIIA gene have been utilized. Furthermore, mutated and tagged versions of GluRIIA have been examined in the past, but most of these constructs were not expressed under endogenous regulatory control or involved the mentioned imprecise GluRIIA knockouts. We performed CRISPR/Cas9-assisted gene editing at the endogenous locus of GluRIIA. This enabled the investigation of the endogenous expression pattern of GluRIIA using tagged constructs with an EGFP and an ALFA tag for super-resolution immunofluorescence imaging, including structured illumination microscopy (SIM) and direct stochastic optical reconstruction microscopy (dSTORM). All GluRIIA constructs exhibited full functionality and PHP could be induced by philanthotoxin at control levels. By applying hierarchical clustering algorithms to analyze the dSTORM data, we detected postsynaptic receptor cluster areas of ~0.15 µm2. Consequently, our constructs are suitable for ultrastructural analyses of GluRIIA.

Environmental enrichment improves social isolation-induced memory impairment: The possible role of ITSN1-Reelin-AMPA receptor signaling pathway.

Environmental enrichment (EE) through combination of social and non-biological stimuli enhances activity-dependent synaptic plasticity and improves behavioural performance. Our earlier studies have suggested that EE resilience the stress induced depression/ anxiety-like behaviour in Indian field mice Mus booduga. This study was designed to test whether EE reverses the social isolation (SI) induced effect and improve memory. Field-caught mice M. booduga were subjected to behaviour test (Direct wild, DW), remaining animals were housed under SI for ten days and then housed for short-term at standard condition (STSC)/ long-term at standard condition (LTSC) or as group in EE cage. Subsequently, we have examined reference, working memory and expression of genes associated with synaptic plasticity. Our analysis have shown that EE reversed SI induced impairment in reference, working memory and other accompanied changes i.e. increased level of Intersectin 1 (ITSN1), Huntingtin (Htt), Synaptotagmin -IV (SYT4), variants of brain-derived neurotrophic factor (Bdnf - III), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (GluR1) expression, and decreased variants of Bdnf (IV), BDNF, Reelin, Apolipoprotein E receptor 2 (ApoER2), very low-density lipoprotein receptor (VLDLR), Src family tyrosine kinase (SFKs), Disabled protein (Dab)-1, Protein kinase B (PKB/Akt), GluR2, Mitogen-activated protein kinase (MAPK) and Extracellular signal-regulated kinase (ERK1/2) expression. In addition, SI induced reduction in BDNF expressing neurons in dentate gyrus of hippocampus reversed by EE. Further, we found that SI decreases small neuro-active molecules such as Benzenedicarboxylic acid, and increases 2-Pregnene in the hippocampus and feces reversed by EE. Overall, this study demonstrated that EE is effectively reversed the SI induced memory impairment by potentially regulating the molecules associated with the ITSN1-Reelin-AMPA receptor pathway to increase synaptic plasticity.

Divergent Learning-Related Transcriptional States of Cortical Glutamatergic Neurons.

Experience-dependent gene expression reshapes neural circuits, permitting the learning of knowledge and skills. Most learning involves repetitive experiences during which neurons undergo multiple stages of functional and structural plasticity. Currently, the diversity of transcriptional responses underlying dynamic plasticity during repetition-based learning is poorly understood. To close this gap, we analyzed single-nucleus transcriptomes of L2/3 glutamatergic neurons of the primary motor cortex after 3 d motor skill training or home cage control in water-restricted male mice. "Train" and "control" neurons could be discriminated with high accuracy based on expression patterns of many genes, indicating that recent experience leaves a widespread transcriptional signature across L2/3 neurons. These discriminating genes exhibited divergent modes of coregulation, differentiating neurons into discrete clusters of transcriptional states. Several states showed gene expressions associated with activity-dependent plasticity. Some of these states were also prominent in the previously published reference, suggesting that they represent both spontaneous and task-related plasticity events. Markedly, however, two states were unique to our dataset. The first state, further enriched by motor training, showed gene expression suggestive of late-stage plasticity with repeated activation, which is suitable for expected emergent neuronal ensembles that stably retain motor learning. The second state, equally found in both train and control mice, showed elevated levels of metabolic pathways and norepinephrine sensitivity, suggesting a response to common experiences specific to our experimental conditions, such as water restriction or circadian rhythm. Together, we uncovered divergent transcriptional responses across L2/3 neurons, each potentially linked with distinct features of repetition-based motor learning such as plasticity, memory, and motivation.

Deprivation-Induced Plasticity in the Early Central Circuits of the Rodent Visual, Auditory, and Olfactory Systems.

Activity-dependent neuronal plasticity is crucial for animals to adapt to dynamic sensory environments. Traditionally, it has been investigated using deprivation approaches in animal models primarily in sensory cortices. Nevertheless, emerging evidence emphasizes its significance in sensory organs and in subcortical regions where cranial nerves relay information to the brain. Additionally, critical questions started to arise. Do different sensory modalities share common cellular mechanisms for deprivation-induced plasticity at these central entry points? Does the deprivation duration correlate with specific plasticity mechanisms? This study systematically reviews and meta-analyzes research papers that investigated visual, auditory, or olfactory deprivation in rodents of both sexes. It examines the consequences of sensory deprivation in homologous regions at the first central synapse following cranial nerve transmission (vision - lateral geniculate nucleus and superior colliculus; audition - ventral and dorsal cochlear nucleus; olfaction - olfactory bulb). The systematic search yielded 91 papers (39 vision, 22 audition, 30 olfaction), revealing substantial heterogeneity in publication trends, experimental methods, measures of plasticity, and reporting across the sensory modalities. Despite these differences, commonalities emerged when correlating plasticity mechanisms with the duration of sensory deprivation. Short-term deprivation (up to 1 d) reduced activity and increased disinhibition, medium-term deprivation (1 d to a week) involved glial changes and synaptic remodeling, and long-term deprivation (over a week) primarily led to structural alterations. These findings underscore the importance of standardizing methodologies and reporting practices. Additionally, they highlight the value of cross-modal synthesis for understanding how the nervous system, including peripheral, precortical, and cortical areas, respond to and compensate for sensory inputs loss.

Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons

Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of invitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.

DiSCIoser: unlocking recovery potential of arm sensorimotor functions after spinal cord injury by promoting activity-dependent brain plasticity by means of brain-computer interface technology: a randomized controlled trial to test efficacy

BackgroundTraumatic cervical spinal cord injury (SCI) results in reduced sensorimotor abilities that strongly impact on the achievement of daily living activities involving hand/arm function. Among several technology-based rehabilitative approaches, Brain-Computer Interfaces (BCIs) which enable the modulation of electroencephalographic sensorimotor rhythms, are promising tools to promote the recovery of hand function after SCI. The “DiSCIoser” study proposes a BCI-supported motor imagery (MI) training to engage the sensorimotor system and thus facilitate the neuroplasticity to eventually optimize upper limb sensorimotor functional recovery in patients with SCI during the subacute phase, at the peak of brain and spinal plasticity. To this purpose, we have designed a BCI system fully compatible with a clinical setting whose efficacy in improving hand sensorimotor function outcomes in patients with traumatic cervical SCI will be assessed and compared to the hand MI training not supported by BCI.MethodsThis randomized controlled trial will include 30 participants with traumatic cervical SCI in the subacute phase randomly assigned to 2 intervention groups: the BCI-assisted hand MI training and the hand MI training not supported by BCI. Both interventions are delivered (3 weekly sessions; 12 weeks) as add-on to standard rehabilitation care. A multidimensional assessment will be performed at: randomization/pre-intervention and post-intervention. Primary outcome measure is the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) somatosensory sub-score. Secondary outcome measures include the motor and functional scores of the GRASSP and other clinical, neuropsychological, neurophysiological and neuroimaging measures.DiscussionWe expect the BCI-based intervention to promote meaningful cortical sensorimotor plasticity and eventually maximize recovery of arm functions in traumatic cervical subacute SCI. This study will generate a body of knowledge that is fundamental to drive optimization of BCI application in SCI as a top-down therapeutic intervention, thus beyond the canonical use of BCI as assistive tool.Trial registrationName of registry: DiSCIoser: improving arm sensorimotor functions after spinal cord injury via brain-computer interface training (DiSCIoser). Trial registration number: NCT05637775; registration date on the ClinicalTrial.gov platform: 05-12-2022.

Dynamics of Hindmarsh–Rose neurons connected via adaptive memristive synapse

Experimental data suggest that temporal neural activity regulates the synaptic weight, a phenomenon known as activity-dependent synaptic plasticity. Thus far, a diversity of neuronal learning rules have been adopted; a likely one is a Hebbian adaptation based on neuron synchrony. Regarding the growing appeal for coupling neurons through memristors, an element bridging magnetic flux and ion exchange, the existing literature on adapting memristive synapses seems limited. This paper aims to investigate two Hindmarsh–Rose neurons coupled through an adaptive memristor synapse by treating adaptive coupling parameters as bifurcation parameters. The capability of adaptive memristive coupling to generate high periodic and chaotic oscillations in the intrinsic periodic behavior of HR neurons is revealed. Synchronization analysis suggests that bifurcation scenarios are closely associated with the transition of the generic firings of two neurons from asynchrony to perfect synchrony. The Hamilton energy analysis indicates that as two neurons transition to synchrony, their energy levels equalize, and the energy fluctuations within the memristive coupling channel diminish. The value of the adaption parameter by which neurons synchronize also depends on the intrinsic parameters of HR, particularly the one associated with the effectiveness of slow channels. Additionally, the synchronization's robustness against different noise intensities has been examined. At last, on the matter of multistability, several pieces of evidence also exist.

54 Exploring the Impact of Stria Terminalis Connectivity and Family Income on Depressive Symptoms Throughout Development

Objective:The stria terminalis (ST) is a white matter tract with connections to limbic and autonomic brain structures that is implicated in affective functioning. Recent works suggests that ST functional integrity and connectivity is associated with faster responses to emotional cues (Dzafic et al., 2019) and may be influenced by environmental factors including socioeconomic status (SES) and childhood adversity (Banihashemi et al., 2020). The role of the ST in the experience of more daily affective experiences, such as depressive symptoms, remains unexplored. Therefore, the present study examined the role of the ST and SES, as assessed by household income, in the relationship between age and depressive symptoms in typically developing children and adolescents.Participants and Methods:Participants include 64 typically developing children and adolescents age 8-21 (Mage=13.27, SD=3.15) who participated in an ongoing study of development of neurocognitive and social-cognitive skills. Participants completed imaging on a 3Tesla MR Siemens PRISMA scanner. Tractography was executed via ENIGMA tract-based spatial statistics to quantify WM integrity and provided values for mean fractional anisotropy (mFA) of the ST. Depressive symptoms were measured with the Behavior Assessment Scale for Children-Third Edition (BASC-3) parent report scale, and annual family income was obtained per parent report. Mediation and moderation analyses were conducted using Process version 4.1 (Hayes, 2022) in SPSS version 28. As depression symptoms are often higher in early adolescence than later, we examined the indirect effect of age on depressive symptoms through ST mFA and evaluated this relationship at different levels of family income.Results:Age was associated with lower levels of depressive symptoms (b=-.98, t=-2.18, p<.05), whereas greater right ST mFA was associated with higher levels of depressive symptoms (b=42.05, t=2.50, p<.05). Right ST mFA explained significant variance in the relationship between age and parent-reported depression (ab=.13, 95% CI [.02, .29]). The conditional indirect effect of family income was significant for children with annual family incomes between 25-50k (effect=.16, 95% CI [.01, .38]) and 75-100k (effect=.13, 95% CI [.001, .31]), but not for 100k+ (effect=.11, 95% CI [-.05, .33]).Conclusions:The present study revealed a significant, positive relationship between white matter integrity in the right ST and parent-reported depressive symptoms in healthy children and young adults. Finding extend on prior work implicating the ST in threat responsivity (Dzafic et al., 2019). Moreover,results suggest the role of the ST in the relationship between age and depression depends on level of family income, such that ST mFA explains more variance at lower income levels, and is no longer significant for children from families with income greater than 100k. These findings support the notion that environmental stressors (such as lower family income) may strengthen ST pathways via activity-dependent plasticity and repeated, coordinated activation (Rinaman et al., 2011). Future studies should examine these brain-behavior associations, as they may replicate in a larger sample, with more nuanced indicators of environmental stress.

Short-term Dendritic Dynamics of Neonatal Cortical Neurons Revealed by in vivo Imaging with Improved Spatiotemporal Resolution.

Individual neurons in sensory cortices exhibit specific receptive fields based on their dendritic patterns. These dendritic morphologies are established and refined during the neonatal period through activity-dependent plasticity. This process can be visualized using two-photon in vivo time-lapse imaging, but sufficient spatiotemporal resolution is essential. We previously examined dendritic patterning from spiny stellate (SS) neurons, the major type of layer 4 (L4) neurons, in the mouse primary somatosensory cortex (barrel cortex), where mature dendrites display a strong orientation bias toward the barrel center. Longitudinal imaging at 8-h intervals revealed the long-term dynamics by which SS neurons acquire this unique dendritic pattern. However, the spatiotemporal resolution was insufficient to detect the more rapid changes in SS neuron dendrite morphology during the critical neonatal period. In the current study, we imaged neonatal L4 neurons hourly for 8 h and improved the spatial resolution by uniform cell-surface labeling. The improved spatiotemporal resolution allowed detection of precise changes in dendrite morphology and revealed aspects of short-term dendritic dynamics unique to the neonatal period. Basal dendrites of barrel cortex L4 neurons were highly dynamic. In particular, both barrel-inner and barrel-outer dendrites (trees and branches) emerged/elongated and disappeared/retracted at similarly high frequencies, suggesting that SS neurons acquire biased dendrite patterns through rapid trial-and-error emergence, elongation, elimination, and retraction of dendritic trees and branches. We also found correlations between morphology and behavior (elongation/retraction) of dendritic tips. Thus, the current study revealed short-term dynamics and related features of cortical neuron dendrites during refinement.Significance StatementThe formation of proper dendritic patterns during early postnatal development is essential for normal neuronal circuit function in adulthood. To elucidate the mechanisms responsible for this refinement, in vivo imaging with high spatiotemporal resolution is useful. Our previous long-term in vivo imaging studies have clarified aspects of dendritic refinement mechanism; however, due to the long intervals (8-h) between image acquisitions, rapid changes in dendritic morphology were missed. Here hourly in vivo time-lapse imaging of neonatal mouse barrel cortex over 8 h revealed the rapid changes in the dendrite morphology of layer 4 neurons, thereby providing a more comprehensive record of dendritic refinement during postnatal development for mechanistic analysis.

Attractor dynamics with activity-dependent plasticity capture human working memory across time scales

Most cognitive functions require the brain to maintain immediately preceding stimuli in working memory. Here, using a human working memory task with multiple delays, we test the hypothesis that working memories are stored in a discrete set of stable neuronal activity configurations called attractors. We show that while discrete attractor dynamics can approximate working memory on a single time scale, they fail to generalize across multiple timescales. This failure occurs because at longer delay intervals the responses contain more information about the stimuli than can be stored in a discrete attractor model. We present a modeling approach that combines discrete attractor dynamics with activity-dependent plasticity. This model successfully generalizes across all timescales and correctly predicts intertrial interactions. Thus, our findings suggest that discrete attractor dynamics are insufficient to model working memory and that activity-dependent plasticity improves durability of information storage in attractor systems.

Do Place Cells Dream of Deceptive Moves in a Signaling Game?

We consider the possibility of applying game theory to analysis and modeling of neurobiological systems. Specifically, the basic properties and features of information asymmetric signaling games are considered and discussed as having potential to explain diverse neurobiological phenomena; we focus on neuronal action potential discharge that can represent cognitive variables in memory and purposeful behavior. We begin by arguing that there is a pressing need for conceptual frameworks that can permit analysis and integration of information and explanations across many scales of biological function including gene regulation, molecular and biochemical signaling, cellular and metabolic function, neuronal population, and systems level organization to generate plausible hypotheses across these scales. Developing such integrative frameworks is crucial if we are to understand cognitive functions like learning, memory, and perception. The present work focuses on systems neuroscience organized around the connected brain regions of the entorhinal cortex and hippocampus. These areas are intensely studied in rodent subjects as model neuronal systems that undergo activity-dependent synaptic plasticity to form neuronal circuits and represent memories and spatial knowledge used for purposeful navigation. Examples of cognition-related spatial information in the observed neuronal discharge of hippocampal place cell populations and medial entorhinal head-direction cell populations are used to illustrate possible challenges to information maximization concepts. It may be natural to explain these observations using the ideas and features of information asymmetric signaling games.

Protein kinase A-dependent plasticity of local inhibitory synapses from hilar somatostatin-expressing neurons.

Hippocampal Inhibitory Neurons (INs) contact local targets and project to different brain areas to form synapses on distal neurons. Despite the importance of INs for hippocampal function and interregional brain communication, the impact of activity-dependent plasticity mechanisms on local and long-range GABAergic synapses formed by hippocampal INs remains to be fully elucidated. Here, we use optogenetic-coupled electrophysiology in mice to show that protein kinase A (PKA), a master regulator of GABAergic synapse plasticity, causes a form of long-term potentiation of inhibitory synapses (iLTP) in hippocampal granule cells (GCs). This form of iLTP is observed in GCs synapses originated in local INs expressing the marker somatostatin (SST) but not in those expressing parvalbumin (PV). Long-range synapses formed by SST INs onto medial septum neurons are unaffected by PKA activation. iLTP of local SST synapses on GCs is accompanied by changes in presynaptic probability of release and is occluded by pharmacological increase of synaptic activity in vivo Our results suggest that PKA-dependent inhibitory synapse plasticity is expressed in local but not long-range targets of SST INs and selectively modifies inhibitory microcircuits essential for hippocampal function.Significance StatementThe hippocampus, a brain region essential for memory, is populated by a diverse group of inhibitory neurons (INs) that form synaptic contacts onto local principal cells and long-range targets. Changes in inhibitory synapse strength shape local and inter-regional brain communication. However, how synapse plasticity mechanisms are implemented in the rich assortment of hippocampal INs remains to be fully defined. Here we show that protein kinase A, a signaling protein involved in memory, enhances inhibitory neurotransmission from local but not long-range projecting hippocampal INs expressing the molecular marker somatostatin. The consequences of this plasticity are observed after increasing neuronal activity in vivo Our work describes a form of activity-dependent synapse plasticity that regulates inhibitory microcircuits essential for hippocampal memory function.